Highly pure phentolamine mesylate and methods for making same

ABSTRACT

This invention provides methods for synthesizing phentolamine mesylate from phentolamine and methanesulfonic acid in the presence of acetone and water. The methods of the present invention provide highly pure phentolamine mesylate. The invention also provides highly pure phentolamine mesylate.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.63/189,839, filed May 18, 2021, and of Chinese Application No.202110679032.9, filed Jun. 18, 2021, the disclosure of each of which isincorporated by reference herein in its entirety.

FIELD OF THE INVENTION

This invention provides methods for synthesizing phentolamine mesylatefrom phentolamine and methanesulfonic acid in the presence of acetoneand water. The methods of the present invention provide highly purephentolamine mesylate. The invention also provides highly purephentolamine mesylate.

BACKGROUND OF THE INVENTION

Phentolamine mesylate is a nonselective alpha adrenergic receptorantagonist approved for use by the Food and Drug Administration (FDA)for reversing soft-tissue anesthesia. Phentolamine mesylate was alsoapproved by the FDA for use in preventing or controlling hypertensiveepisodes in patients with pheochromocytoma and for treatment of dermalnecrosis following intravenous administration or extravasation ofnorepinephrine.

Phentolamine mesylate continues to be studied for new indications. Thus,an improved synthesis of phentolamine to produce highly pure product isdesired.

SUMMARY OF THE INVENTION

The present invention provides methods for making phentolamine mesylate,comprising:

(a) allowing Compound 1

to react with methanesulfonic acid in the presence of acetone and waterunder conditions effective to make a first mixture comprisingphentolamine mesylate;

(b) admixing to the first mixture and methyl t-butyl ether to make asecond mixture; and

(c) allowing the phentolamine mesylate to precipitate from the secondmixture (each method being a “synthesis method of the invention”).

The present invention further provides phentolamine mesylate that ismade by a synthesis method of the invention, has a purity obtainable bya synthesis method of the invention or exhibits an X-ray powderdiffraction (XRPD) pattern obtainable by a synthesis method of theinvention (the phentolamine mesylate being a “compound of theinvention”).

The present invention further provides phentolamine mesylate thatexhibits an XRPD pattern comprising a peak at about 6.87±0.2 degrees2-theta, a peak at about 20.32±0.2 degrees 2-theta, and a peak at about21.36±0.2 degrees 2-theta.

The present invention further provides compositions comprising aneffective amount of a compound of the invention (each composition beinga “composition of the invention”).

The present invention further provides methods for inhibitingcontraction of smooth muscle of the iris, comprising administering to asubject in need thereof an effective amount of a compound of theinvention.

The present invention further provides methods for reducing pupildiameter, comprising administering to a subject in need thereof aneffective amount of a compound of the invention.

The present invention further provides methods for improving visualcontrast sensitivity or visual acuity, comprising administering to asubject in need thereof an effective amount of a compound of theinvention.

The present invention further provides methods for treating a dim ornight vision disturbance, comprising administering to a subject in needthereof an effective amount of a compound of the invention.

The present invention further provides methods for treating or reversingpharmacologically induced mydriasis, comprising administering to asubject in need thereof an effective amount of a compound of theinvention.

The present invention further provides methods for treating presbyopia,comprising administering to a subject in need thereof an effectiveamount of a compound of the invention.

Each of the methods for inhibiting contraction of smooth muscle of theiris, reducing pupil diameter, improving visual contrast sensitivity orvisual acuity, treating a dim or night vision disturbance, treating orreversing pharmacologically induced mydriasis or treating presbyopia isa “therapeutic method of the invention”.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an XRPD pattern of a phentolamine mesylate obtained asdescribed in Example 2.

FIG. 2 shows an overlay of a thermo-gravimetric (TG) thermogram and adifferential scanning calorimetry (DSC) thermogram of phentolaminemesylate obtained as described in Example 2.

FIG. 3 shows an XRPD pattern of a phentolamine mesylate United StatesPharmacopeia (USP) reference standard.

FIG. 4 shows an overlay of a TG thermogram of a phentolamine mesylateUSP reference standard and a DSC thermogram of phentolamine mesylate USPreference standard.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The term “about” when immediately preceding a numerical value means ±upto 20% of the numerical value. For example, “about” a numerical valuemeans ±up to 20% of the numerical value, in some embodiments, ±up to19%, ±up to 18%, ±up to 17%, ±up to 16%, ±up to 15%, ±up to 14%, ±up to13%, ±up to 12%, ±up to 11%, ±up to 10%, ±up to 9%, ±up to 8%, ±up to7%, ±up to 6%, ±up to 5%, ±up to 4%, ±up to 3%, ±up to 2%, ±up to 1%,±up to less than 1%, or any other value or range of values therein.

Throughout the present specification, numerical ranges are provided forcertain quantities. These ranges comprise all subranges therein. Thus,the range “from 50 to 80” includes all possible ranges therein (e.g.,51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all valueswithin a given range may be an endpoint for the range encompassedthereby (e.g., the range 50-80 includes the ranges with endpoints suchas 55-80, 50-75, etc.).

The term “pharmaceutically acceptable salt” includes both an acid and abase addition salt. Pharmaceutically acceptable salts can be obtained byreacting a compound of the invention functioning as a base, with aninorganic or organic acid to form a salt, for example, salts ofhydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid,camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citricacid, formic acid, hydrobromic acid, benzoic acid, tartaric acid,fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc.Pharmaceutically acceptable salts can also be obtained by reacting acompound of the invention functioning as an acid, with an inorganic ororganic base to form a salt, for example, salts of sodium, potassium,lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese,aluminum, ammonia, isopropylamine, trimethylamine, etc. In someembodiments, the pharmaceutically acceptable salt is a zinc salt. Thoseskilled in the art will further recognize that pharmaceuticallyacceptable salts can be prepared by reaction of the compounds of theinvention with an appropriate inorganic or organic acid or base via anyof a number of known methods.

The term “solvate” refers to a solvation complex. Solvates can be formedby solvation (the combination of solvent molecules with molecules orions of the compounds of the invention), or a solvate can be anaggregate that comprises a solute ion or molecule or a solvent molecule.The solvent can be water, in which case the solvate is a hydrate.Examples of hydrates include, but are not limited to, a hemihydrate,monohydrate, dihydrate, trihydrate, hexahydrate, etc. The solvate can beformed via hydration, including via absorption of moisture. Apharmaceutically acceptable salt can also be a solvate. Where a solvateis obtained via crystallization from a solvent, the solvent can be analcohol, such as methanol or ethanol; an aldehyde; a ketone, such asacetone; or an ester, such as ethyl acetate.

The term “effective amount” refers to an amount of a compound of theinvention that is effective to inhibit contraction of smooth muscle ofthe iris, reduce pupil diameter, improve visual contrast sensitivity orvisual acuity, treat a dim or night vision disturbance or treat orreverse pharmacologically induced mydriasis in a subject in needthereof.

All weight percentages (i.e., “% by weight” and “wt. %” and w/w)referenced herein, unless otherwise indicated, are relative to the totalweight of the mixture or composition, as the case may be.

As used herein, an “impurity” is a compound or substance other thanphentolamine mesylate.

As used herein, “isolated” means isolated from a chemical synthesisreaction mixture. In some embodiments, isolated phentolamine mesylate isat least 95% pure and comprises no more than 5% of one or moreimpurities. By “is at least x % pure” means that a compound of theinvention includes no more than (100−x) % of one or more impurities. Insome embodiments, isolated phentolamine mesylate is at least 96%, atleast 97%, at least 98%, or at least 99% pure, and comprises no morethan 4%, no more than 3%, no more than 2%, or no more than 1% of animpurity, respectively. In some embodiments, the one or more impurities,if any, are present in the phentolamine mesylate as a percent by weight.In some embodiments, the one or more impurities, if any, are present inthe phentolamine mesylate as a percent by mole. In some embodiments, theone or more impurities, if any, are present in the phentolamine mesylateas a percent by volume.

As used herein, “substantially the same as” when used in connection withan XRPD pattern means that that each peak of the XRPD pattern differsfrom a respective peak of a stated reference compound by no more than±0.2 degrees 2-theta, in some embodiments, no more than ±0.1 degree2-theta.

As used herein, “substantially the same as” when used in connection witha DSC thermogram means that that each peak of the DSC thermogram differsfrom a respective peak of a stated reference compound by no more than±3° C., in some embodiments, no more than ±2° C.

As used herein, “substantially the same as” when used in connection witha TG thermogram means that that each peak of the TG thermogram differsfrom a respective peak of a stated reference compound by no more than±3° C., in some embodiments, no more than ±2° C.

Synthesis Methods of the Invention

The present invention provides methods for making phentolamine mesylate,comprising:

-   -   (a) allowing Compound 1

to react with methanesulfonic acid in the presence of acetone and waterunder conditions effective to make a first mixture comprisingphentolamine mesylate;

-   -   (b) admixing the first mixture and methyl t-butyl ether to make        a second mixture; and    -   (c) allowing the phentolamine mesylate to precipitate from the        second mixture.

In some embodiments of the synthesis methods of the invention, themethods further comprise the step of: (d) isolating the phentolaminemesylate from the second mixture, wherein the isolating providesisolated phentolamine mesylate. In some embodiments, the isolating isfiltering, and the isolated phentolamine mesylate is filteredphentolamine mesylate. In some embodiments, the filtered phentolaminemesylate is washed with methyl t-butyl ether.

In some embodiments of the synthesis methods of the invention, themethods further comprise the step of: (e) drying the isolatedphentolamine mesylate to provide dried phentolamine mesylate. In someembodiments, the isolated phentolamine or filtered phentolamine is driedusing a rotary evaporator. In some embodiments, the isolatedphentolamine or filtered phentolamine is dried using a rotary evaporatorand at a temperature of about 30° C. to about 50° C. In someembodiments, the isolated phentolamine or filtered phentolamine is driedusing a rotary evaporator and at a temperature of about 30° C. to about40° C. In some embodiments, the drying comprises lyophilizing. In someembodiments, the drying comprises drying using a rotary evaporator andsubsequently lyophilizing. In some embodiments, the drying is continueduntil a weight loss on drying is not more than 0.5% of the weight of theisolated phentolamine mesylate subjected to drying.

In some embodiments, the drying is performed at a pressure ranging fromabout 0.001 mbar to about 1000 mbar. In some embodiments, the drying isperformed at a pressure ranging from about 1 mbar to about 1000 mbar. Insome embodiments, the drying is performed at a pressure ranging fromabout 1 mbar to about 500 mbar. In some embodiments, the drying isperformed at a pressure ranging from about 1 mbar to about 200 mbar. Insome embodiments, the drying is performed at a pressure ranging fromabout 1 mbar to about 100 mbar. In some embodiments, the drying isperformed at a pressure ranging from about 1 mbar to about 50 mbar. Insome embodiments, the drying is performed at a pressure ranging fromabout 0.001 mbar to about 1 mbar. In some embodiments, the drying isperformed at a pressure ranging from about 0.001 mbar to about 0.75mbar. In some embodiments, the drying is performed at a pressure rangingfrom about 0.001 mbar to about 0.5 mbar. In some embodiments, the dryingis performed at a pressure ranging from about 0.005 mbar to about 0.75mbar. In some embodiments, the drying is performed at a pressure rangingfrom about 0.01 mbar to about 0.75 mbar. In some embodiments, the dryingis performed at a pressure ranging from about 0.05 mbar to about 0.75mbar. In some embodiments, the drying is performed at a pressure rangingfrom about 0.05 mbar to about 0.5 mbar. In some embodiments, the dryingis performed at a pressure of about 40 mbar.

In some embodiments, the lyophilizing is performed at a temperature ofabout −78° C. to about 0° C. In some embodiments, the lyophilizingperformed at a temperature of about −50° C. to about 0° C. In someembodiments, the lyophilizing performed at a temperature of about −50°C. to about −10° C. In some embodiments, the lyophilizing performed at atemperature of about 0° C., about −5° C., about −10° C., about −15° C.,about −20° C., about −25° C., about −30° C., about −35° C., about −40°C., about −45° C., about −50° C., about −55° C., about −60° C., about−65° C., about −70° C., about −75° C., or about −78° C. In someembodiments, the temperature is the temperature inside a vessel thatcontains the phentolamine mesylate. In some embodiments, the temperatureis the temperature outside of a vessel that contains the phentolaminemesylate. In some embodiments, the temperature is that of a cooling bathor an interior of a cooling jacket or refrigeration device.

In some embodiments, the lyophilizing is performed at a pressure rangingfrom about 0.001 mbar to about 1000 mbar. In some embodiments, thelyophilizing is performed at a pressure ranging from about 1 mbar toabout 1000 mbar. In some embodiments, the lyophilizing is performed at apressure ranging from about 1 mbar to about 500 mbar. In someembodiments, the lyophilizing is performed at a pressure ranging fromabout 1 mbar to about 200 mbar. In some embodiments, the lyophilizing isperformed at a pressure ranging from about 1 mbar to about 100 mbar. Insome embodiments, the lyophilizing is performed at a pressure rangingfrom about 1 mbar to about 50 mbar. In some embodiments, thelyophilizing is performed at a pressure ranging from about 0.001 mbar toabout 1 mbar. In some embodiments, the lyophilizing is performed at apressure ranging from about 0.001 mbar to about 0.75 mbar. In someembodiments, the lyophilizing is performed at a pressure ranging fromabout 0.001 mbar to about 0.5 mbar. In some embodiments, thelyophilizing is performed at a pressure ranging from about 0.005 mbar toabout 0.75 mbar. In some embodiments, the lyophilizing is performed at apressure ranging from about 0.01 mbar to about 0.75 mbar. In someembodiments, the lyophilizing is performed at a pressure ranging fromabout 0.05 mbar to about 0.75 mbar. In some embodiments, thelyophilizing is performed at a pressure ranging from about 0.05 mbar toabout 0.5 mbar. In some embodiments, the lyophilizing is performed at apressure of about 40 mbar.

In some embodiments, the lyophilizing is performed at a pressure rangingfrom about 50 mTorr to about 400 mTorr. In some embodiments, thelyophilizing is performed at a pressure ranging from about 100 mTorr toabout 350 mTorr. In some embodiments, the lyophilizing is performed at apressure ranging from about 100 mTorr to about 300 mTorr. In someembodiments, the lyophilizing is performed at a pressure ranging fromabout 100 mTorr to about 200 mTorr. In some embodiments, thelyophilizing is performed at a pressure of about 50 mTorr, about 75mTorr, about 100 mTorr, about 125 mTorr, about 150 mTorr, about 175mTorr, about 200 mTorr, about 225 mTorr, about 250 mTorr, about 275mTorr, about 300 mTorr, about 325 mTorr, about 350 mTorr, about 375mTorr, or about 400 mTorr.

In some embodiments, the lyophilizing is performed for about 30 minutesto about 7 days. In some embodiments, the lyophilizing is performed forabout 30 minutes to about 5 days. In some embodiments, the lyophilizingis performed for about 30 minutes to about 3 days. In some embodiments,the lyophilizing is performed for about 30 minutes to about 24 hours. Insome embodiments, the lyophilizing is performed for about 30 minutes toabout 12 hours. In some embodiments, the lyophilizing is performed forabout 30 minutes to about 6 hours. In some embodiments, the lyophilizingis performed for about 30 minutes to about 3 hours. In some embodiments,the lyophilizing is performed for about 30 minutes, about 45 minutes,about 60 minutes, about 75 minutes, about 90 minutes, about 105 minutes,about 120 minutes, about 135 minutes, about 150 minutes, about 165minutes, or about 180 minutes. In some embodiments, the lyophilizing isperformed for about 30 minutes, about 1 hour, about 2 hours, about 3hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours,about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours,about 22 hours, about 23 hours, about 24 hours, about 26 hours, about 28hours, about 30 hours, about 32 hours, about 34 hours, about 36 hours,about 38 hours, about 40 hours, about 42 hours, about 44 hours, about 46hours, about 48 hours, about 50 hours, about 52 hours, about 54 hours,about 56 hours, about 58 hours, about 60 hours, about 62 hours, about 64hours, about 66 hours, about 68 hours, about 70 hours, or about 72hours. In some embodiments, the time described herein for thelyophilization is the time for one or more lyophilization cycles. In oneembodiment, the lyophilizing is performed using 1, 2, 3, 4, 5, 6, 7, 8,9, or 10 lyophilization cycles. In one embodiment, the lyophilizingcomprises an annealing step.

In some embodiments, the lyophilizing is performed with stirring. Insome embodiments, the lyophilizing is performed without stirring.

In some embodiments of the synthesis methods of the invention, the ratioof acetone to water is about 5:1 acetone:water by volume to about 15:1acetone:water by volume. In some embodiments, the ratio of acetone towater is about 10:1 acetone:water by volume to about 12:1 acetone:waterby volume. In some embodiments, the ratio of acetone to water is about11:1 acetone:water by volume. In some embodiments, the ratio of acetoneto water is about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about10:1, about 11:1, about 12:1, about 13:1, about 14:1, or about 15:1acetone:water by volume.

In some embodiments of the synthesis methods of the invention, theconcentration of Compound 1 is about 0.2 moles/liter of the acetone andwater to about 0.4 moles/liter of the acetone and water. In someembodiments, the concentration of Compound 1 is about 0.3 moles/liter ofthe acetone and water. In some embodiments, the concentration ofCompound 1 is about 0.2 moles/liter, about 0.25 moles/liter, about 0.3moles/liter, about 0.35 moles/liter, or about 0.4 moles/liter of theacetone and water.

In some embodiments of the synthesis methods of the invention, theacetone and water does not comprise a detectable amount of an alcoholsolvent. In some embodiments of the synthesis methods of the invention,the acetone and water comprise less than about 1%, less than about 0.5%,less than about 0.1%, or less than about 0.01% of an alcohol solvent byweight of the acetone and water. In some embodiments of the synthesismethods of the invention, the first mixture does not comprise adetectable amount of an alcohol solvent. In some embodiments of thesynthesis methods of the invention, the first mixture comprises lessthan about 1%, less than about 0.5%, less than about 0.1%, or less thanabout 0.01% of an alcohol solvent by weight of the first mixture. Insome embodiments of the synthesis methods of the invention, the secondmixture does not comprise a detectable amount of an alcohol solvent. Insome embodiments of the synthesis methods of the invention, the secondmixture comprises less than about 1%, less than about 0.5%, less thanabout 0.1%, or less than about 0.01% of an alcohol solvent by weight ofthe second mixture. In some embodiments of the synthesis methods of theinvention, the acetone and water, the first mixture and the secondmixture do not comprise a detectable amount of an alcohol solvent. Insome embodiments, the synthesis methods of the invention are performedin the absence of a detectable amount of an alcohol solvent. In someembodiments of the synthesis methods of the invention, the acetone andwater, the first mixture and the second mixture comprise less than about1%, less than about 0.5%, less than about 0.1%, or less than about 0.01%of an alcohol solvent by weight of the acetone and water, the firstmixture, or the second mixture. In some embodiments, the synthesismethods of the invention are performed in the absence of a detectableamount of an alcohol solvent. In some embodiments, the alcohol solventis isopropanol, n-propanol, ethanol, or methanol.

In some embodiments of the synthesis methods of the invention, theacetone and water does not comprise toluene. In some embodiments of thesynthesis methods of the invention, the first mixture does not comprisetoluene. In some embodiments of the synthesis methods of the invention,the second mixture does not comprise toluene. In some embodiments of thesynthesis methods of the invention, the acetone and water, the firstmixture and the second mixture do not comprise toluene. In someembodiments, the synthesis methods of the invention are performed in theabsence of a detectable amount of toluene. In some embodiments, thesynthesis methods of the invention are performed in the absence of adetectable amount of an alcohol solvent and toluene.

In some embodiments of the synthesis methods of the invention, theacetone and water is at or is adjusted to a temperature of about 15° C.to about 25° C. In some embodiments, the acetone and water is at or isadjusted to a temperature of about 15° C. to about 25° C. immediatelybefore allowing Compound 1 to react with methanesulfonic acid.

In some embodiments of the synthesis methods of the invention, Compound1 and the acetone and water form a solution, and the methanesulfonicacid is added to the solution. In some embodiments, Compound 1 and theacetone and water form a solution, and the methanesulfonic acid is addeddropwise to the solution. In some embodiments, Compound 1 and theacetone and water form a solution, the methanesulfonic acid is added tothe solution and the addition of methanesulfonic acid causes thetemperature of the solution to rise to about 40° C. to about 50° C. Insome embodiments, Compound 1 and the acetone and water form a solution,the methanesulfonic acid is added to the solution and after the completeaddition of methanesulfonic acid, the first mixture is allowed to stirfor about 30 minutes. In some embodiments, Compound 1 and the acetoneand water form a solution, the methanesulfonic acid is added to thesolution and after the complete addition of methanesulfonic acid, thefirst mixture is allowed to stir for at least about 30 minutes.

In some embodiments of the synthesis methods of the invention, Compound1 and the acetone and water form a solution, and the solution is addedto the methanesulfonic acid. In some embodiments, Compound 1 and theacetone and water form a solution, and the solution is added dropwise tothe methanesulfonic acid. In some embodiments, Compound 1 and theacetone and water form a solution, the solution is added to themethanesulfonic acid and the addition of the solution causes thetemperature of the solution to rise to about 40° C. to about 50° C. Insome embodiments, Compound 1 and the acetone and water form a solution,the solution is added to the methanesulfonic acid and after the completeaddition of solution, the first mixture is allowed to stir for about 30minutes. In some embodiments, Compound 1 and the acetone and water forma solution, the solution is added to the methanesulfonic acid and afterthe complete addition of solution, the first mixture is allowed to stirfor at least about 30 minutes.

In some embodiments of the synthesis methods of the invention, Compound1 and the acetone and water form a suspension, and the methanesulfonicacid is added to the suspension. In some embodiments, Compound 1 and theacetone and water form a suspension, and the methanesulfonic acid isadded dropwise to the suspension. In some embodiments, Compound 1 andthe acetone and water form a suspension, the methanesulfonic acid isadded to the suspension and the addition of methanesulfonic acid causesthe temperature of the suspension to rise to about 40° C. to about 50°C. In some embodiments, Compound 1 and the acetone and water form asuspension, the methanesulfonic acid is added to the suspension andafter the complete addition of methanesulfonic acid, the first mixtureis allowed to stir for about 30 minutes. In some embodiments, Compound 1and the acetone and water form a suspension, the methanesulfonic acid isadded to the suspension and after the complete addition ofmethanesulfonic acid, the first mixture is allowed to stir for at leastabout 30 minutes.

In some embodiments of the synthesis methods of the invention, Compound1 and the acetone and water form a suspension, and the suspension isadded to the methanesulfonic acid. In some embodiments, Compound 1 andthe acetone and water form a suspension, and the suspension is addeddropwise to the methanesulfonic acid. In some embodiments, Compound 1and the acetone and water form a suspension, the suspension is added tothe methanesulfonic acid and the addition of the suspension causes thetemperature of the suspension to rise to about 40° C. to about 50° C. Insome embodiments, Compound 1 and the acetone and water form asuspension, the suspension is added to the methanesulfonic acid andafter the complete addition of suspension, the first mixture is allowedto stir for about 30 minutes. In some embodiments, Compound 1 and theacetone and water form a suspension, the suspension is added to themethanesulfonic acid and after the complete addition of suspension, thefirst mixture is allowed to stir for at least about 30 minutes.

In some embodiments of the synthesis methods of the invention, the firstmixture is clear. In this context, “clear” means that all visible solidsare dissolved completely or are no longer visible. In some embodiments,the first mixture is heated at about 45° C. and allowed to stir untilthe first mixture becomes clear. In some embodiments, the first mixtureis heated at about 45° C. and allowed to stir at about 45° C. until thefirst mixture becomes clear.

In some embodiments of the synthesis methods of the invention, themethods comprise allowing 1 molar equivalent of Compound 1 to react withabout 0.9 molar equivalent to about 1.5 molar equivalent ofmethanesulfonic acid. In some embodiments, the synthesis methodscomprise allowing 1 molar equivalent of Compound 1 to react with about1.1 molar equivalent of methanesulfonic acid. In some embodiments, thesynthesis methods comprise allowing 1 molar equivalent of Compound 1 toreact with about 0.9 molar equivalent, about 1.0 molar equivalent, about1.1 molar equivalent, about 1.2 molar equivalent, about 1.3 molarequivalent, about 1.4 molar equivalent, or about 1.5 molar equivalent ofmethanesulfonic acid.

In some embodiments, the admixing comprises adding the methyl t-butylether to the first mixture. In some embodiments, the admixing comprisesadding the first mixture to the methyl t-butyl ether.

In some embodiments of the synthesis methods of the invention, the firstmixture is at or is adjusted to a temperature of about 15° C. to about25° C. immediately before admixing the first mixture and methyl t-butylether.

In some embodiments of the synthesis methods of the invention, allowingphentolamine mesylate to precipitate from the second mixture comprisescooling the second mixture to a temperature of about 15° C. to about−25° C. In some embodiments, allowing phentolamine mesylate toprecipitate from the second mixture comprises cooling the second mixtureto a temperature of about 15° C. to about −15° C. In some embodiments,allowing phentolamine mesylate to precipitate from the second mixturecomprises cooling the second mixture to a temperature of about 5° C. toabout −25° C. In some embodiments, allowing phentolamine mesylate toprecipitate from the second mixture comprises cooling the second mixtureto a temperature of about 5° C. to about −15° C. In some embodiments,allowing phentolamine mesylate to precipitate from the second mixturecomprises cooling the second mixture to a temperature of about 15° C. toabout 8° C. In some embodiments, allowing phentolamine mesylate toprecipitate from the second mixture comprises cooling the second mixtureto a temperature of about 14° C. to about 5° C. In some embodiments,allowing phentolamine mesylate to precipitate from the second mixturecomprises cooling the second mixture to a temperature of about 0° C. toabout −15° C. In some embodiments, allowing phentolamine mesylate toprecipitate from the second mixture comprises cooling the second mixtureto a temperature of about 3° C. to about −3° C. In some embodiments,allowing phentolamine mesylate to precipitate from the second mixturecomprises cooling the second mixture to a temperature of about 0° C. Insome embodiments, allowing phentolamine mesylate to precipitate from thesecond mixture comprises cooling the methyl t-butyl ether-dilutedmixture to a temperature of about −20° C.

In some embodiments of the synthesis methods of the invention, allowingphentolamine mesylate to precipitate comprises cooling the secondmixture to a first temperature of about 15° C. to about −15° C.,allowing the second mixture to stir at the first temperature for about 1hour, and then further cooling the second mixture to a secondtemperature of about −20° C. In some embodiments, the first temperatureis about 15° C. to about −5° C. In some embodiments, the firsttemperature is about 15° C. to about 0° C. In some embodiments, thefirst temperature is about 14° C. to about 8° C. In some embodiments,the first temperature is about 3° C. to about −3° C.

In some embodiments, the second mixture is cooled to the firsttemperature at an average rate of about 0.5° C./min to about 2° C./min.In some embodiments, the second mixture is cooled to the firsttemperature at an average rate of about 1° C./min to about 1.5° C./min.In some embodiments, the second mixture is cooled to the firsttemperature at an average rate of about 1.33° C./min. In someembodiments, cooling the second mixture to the first temperature takesabout 5 minutes to about 60 minutes. In some embodiments, cooling thesecond mixture to the first temperature takes about 10 minutes to about45 minutes. In some embodiments, cooling the second mixture to the firsttemperature takes about 10 minutes to about 30 minutes. In someembodiments, cooling the second mixture to the first temperature takesabout 15 minutes.

In some embodiments, the second mixture is cooled from the firsttemperature to the second temperature at an average rate of about 0.5°C./min to about 2° C./min. In some embodiments, the second mixture iscooled from the first temperature to the second temperature at anaverage rate of about 0.75° C./min to about 1.5° C./min. In someembodiments, the second mixture is cooled to the second temperature fromthe first temperature at an average rate of about 1° C./min. In someembodiments, cooling the second mixture to the second temperature fromthe first temperature takes about 5 minutes to about 60 minutes. In someembodiments, cooling the second mixture to the second temperature fromthe first temperature takes about 10 minutes to about 45 minutes. Insome embodiments, cooling the second mixture to the second temperaturefrom the first temperature takes about 10 minutes to about 30 minutes.In some embodiments, cooling the second mixture to the secondtemperature from the first temperature takes about 20 minutes.

In some embodiments of the synthesis methods of the invention, themethods are performed in the absence of a detectable amount of an alkylmethanesulfonate. In some embodiments, the methods do not make an alkylmethanesulfonate, e.g., as a by-product or degradation product. In someembodiments, a compound of the invention does not comprise an alkylmethanesulfonate.

In some embodiments, the purity of the methanesulfonic acid is at leastabout 95% (weight %) and the methanesulfonic acid comprises no more thanabout 5% of an impurity (weight %) of the methanesulfonic acid. In someembodiments, the purity of the methanesulfonic acid is at least about97% (weight %) and the methanesulfonic acid comprises no more than about3% of an impurity (weight %) of the methanesulfonic acid. In someembodiments, the purity of the methanesulfonic acid is at least about98% (weight %) and the methanesulfonic acid comprises no more than about2% of an impurity (weight %) of the methanesulfonic acid. In someembodiments, the purity of the methanesulfonic acid is at least about99% (weight %) and the methanesulfonic acid comprises no more than about1% of an impurity (weight %). In some embodiments, the methanesulfonicacid does not comprise a detectable amount of an alkyl methanesulfonate.In some embodiments, the impurity is determined by high-performanceliquid chromatography (HPLC). In some embodiments, the impurity isdetermined by gas chromatography (GC).

In some embodiments, the purity of the acetone is at least about 95%(weight %) and acetone comprises no more than about 5% of an impurity(weight %) of the acetone. In some embodiments, the purity of theacetone is at least about 97% (weight %) and acetone comprises no morethan about 3% of an impurity (weight %) of the acetone. In someembodiments, the purity of the acetone is at least about 98% (weight %)and acetone comprises no more than about 2% of an impurity (weight %) ofthe acetone. In some embodiments, the purity of the acetone is at leastabout 99% (weight %) and acetone comprises no more than about 1% of animpurity (weight %) of the acetone. In some embodiments, the acetonedoes not comprise a detectable amount of an alkyl methanesulfonate. Insome embodiments, the impurity is determined by high-performance liquidchromatography (HPLC). In some embodiments, the impurity is determinedby gas chromatography (GC).

In some embodiments, the purity of the water is at least about 95%(weight %) and water comprises no more than about 5% of an impurity(weight %) of the water. In some embodiments, the purity of the water isat least about 97% (weight %) and water comprises no more than about 3%of an impurity (weight %) of the water. In some embodiments, the purityof the water is at least about 98% (weight %) and water comprises nomore than about 2% of an impurity (weight %) of the water. In someembodiments, the purity of the water is at least about 99% (weight %)and water comprises no more than about 1% of an impurity (weight %) ofthe water. In some embodiments, the water does not comprise a detectableamount of an alkyl methanesulfonate. In some embodiments, the impurityis determined by high-performance liquid chromatography (HPLC).

In some embodiments, the purity of the methyl t-butyl ether is at leastabout 95% (weight %) and methyl t-butyl ether comprises no more thanabout 5% of an impurity (weight %) the methyl t-butyl ether. In someembodiments, the purity of the methyl t-butyl ether is at least about97% (weight %) and methyl t-butyl ether comprises no more than about 3%of an impurity (weight %) the methyl t-butyl ether. In some embodiments,the purity of the methyl t-butyl ether is at least about 98% (weight %)and methyl t-butyl ether comprises no more than about 2% of an impurity(weight %) the methyl t-butyl ether. In some embodiments, the purity ofthe methyl t-butyl ether is at least about 99% (weight %) and methylt-butyl ether comprises no more than about 1% of an impurity (weight %)the methyl t-butyl ether. In some embodiments, the methyl t-butyl etherdoes not comprise a detectable amount of an alkyl methanesulfonate. Insome embodiments, the impurity is determined by high-performance liquidchromatography (HPLC). In some embodiments, the impurity is determinedby gas chromatography (GC).

In some embodiments, Compound 1 does not comprise an impurity. In someembodiments Compound 1 comprises an impurity. In some embodiments, theimpurity is an alkyl methanesulfonate. In some embodiments of thecompounds of the invention, the alkyl methanesulfonate is methylmethanesulfonate, ethyl methanesulfonate, n-propyl methanesulfonate, orisopropyl methanesulfonate. In some embodiments, the impurity is aprocess by-product or a degradation product. In some embodiments, theimpurity is Impurity A(N-(2-aminoethyl)-2-[(3-hydroxyphenyl)(4-methylphenyl)amino]-acetamide):

In some embodiments, the impurity is an Impurity A salt. In someembodiments, the impurity is an Impurity A methanesulfonate salt. Insome embodiments, Impurity A is a by-product or degradation product.

In some embodiments, the impurity is Impurity B(2-chloromethyl-4,5-dihydro-1H-imidazole):

In some embodiments, Impurity B is a process byproduct. In someembodiments, the impurity is an Impurity B salt. In some embodiments,the impurity is an Impurity B methanesulfonate salt.

In some embodiments, the impurity is Impurity C(3-hydroxy-4′-methyldiphenylamine):

In some embodiments, Impurity C is a process by-product or degradationproduct. In some embodiments, Impurity C is a degradation product. Insome embodiments, the impurity is an Impurity C salt. In someembodiments, the impurity is an Impurity C methanesulfonate salt. Insome embodiments, the impurity is one or more of Impurity A, Impurity B,and Impurity C, or a salt thereof. In some embodiments, the salt is amethanesulfonic acid salt.

In some embodiments, the purity of Compound 1 is about 95.0% to 100% byweight, and Compound 1 comprises 0% to about 5.0% of an impurity byweight of Compound 1. In some embodiments, the purity of Compound 1 isabout 98% to 100% by weight, and Compound 1 comprises 0% to about 2% ofan impurity by weight of Compound 1. In some embodiments, the purity ofCompound 1 is about 98%, about 98.5%, about 99%, about 99.5%, or 100% byweight, and Compound 1 comprises about 2%, about 1.5%, about 1%, about0.5%, or 0%, respectively, of an impurity by weight of Compound 1. Insome embodiments, the purity or the impurity are determined byhigh-performance liquid chromatography (HPLC). In some embodiments, theimpurity is determined by titration.

In some embodiments, the purity of Compound 1 is at least about 98% byweight, and Compound 1 comprises no more than about 2% of an impurity byweight of Compound 1, as determined by GC. In some embodiments, thepurity of Compound 1 is about 95.0% to 100% by weight, and comprises 0%to about 5.0% of an impurity by weight of Compound 1, as determined byGC. In some embodiments, the purity of Compound 1 is about 98% to 100%by weight, and Compound 1 comprises 0% to about 2% of an impurity byweight of Compound 1, as determined by GC. In some embodiments, thepurity of Compound 1 is about 98%, about 98.5%, about 99%, about 99.5%,or 100% by weight, and Compound 1 comprises about 2%, about 1.5%, about1%, about 0.5%, or 0% by weight of Compound 1, respectively, of animpurity as determined by GC. In some embodiments, Compound 1 comprisesless than about 0.5% solvent as determined by GC. In some embodiments,Compound 1 comprises less than about 0.3% solvent as determined by GC.

In some embodiments, Compound 1 comprises less than 0.5% by weight of animpurity based on the weight of Compound 1. In some embodiments,Compound 1 comprises less than 0.5% impurity by weight, less than 0.4%impurity by weight, less than 0.3% impurity by weight, less than 0.2%impurity by weight, or less than 0.1% impurity by weight of Compound 1.In some embodiments, Compound 1 comprises no more than 0.5% impurity byweight of Compound 1. In some embodiments, Compound 1 comprises no morethan 0.5% impurity by weight, no more than 0.4%, impurity by weight nomore than 0.3% impurity by weight, no more than 0.2% impurity by weight,or no more than 0.1% impurity by weight of Compound 1. In someembodiments, the impurity is determined by high-performance liquidchromatography (HPLC). In some embodiments, the impurity is determinedby titration.

In some embodiments, the impurity in Compound 1 is an alkylmethanesulfonate. In some embodiments of the compounds of the invention,the alkyl methanesulfonate is methyl methanesulfonate, ethylmethanesulfonate, n-propyl methanesulfonate, or isopropylmethanesulfonate.

In some embodiments, the impurity in Compound 1 is a process by-productor a degradation product.

In some embodiments, the impurity in Compound 1 is Impurity A(N-(2-aminoethyl)-2-[(3-hydroxyphenyl)(4-methylphenyl)amino]-acetamide).In some embodiments, the impurity is an Impurity A salt. In someembodiments, the impurity is an Impurity A methanesulfonate salt.

In some embodiments, Impurity A is a by-product or degradation product.

In some embodiments, the impurity in Compound 1 is Impurity B(2-chloromethyl-4,5-dihydro-1H-imidazole). In some embodiments, ImpurityB is a process byproduct. In some embodiments, the impurity is anImpurity B salt. In some embodiments, the impurity is an Impurity Bmethanesulfonate salt.

In some embodiments, the impurity in Compound 1 is Impurity C(3-hydroxy-4′-methyldiphenylamine). In some embodiments, Impurity C is aprocess by-product or degradation product. In some embodiments, ImpurityC is a degradation product. In some embodiments, the impurity is anImpurity C salt. In some embodiments, the impurity is an Impurity Cmethanesulfonate salt.

In some embodiments, the impurity in Compound 1 is one or more ofImpurity A, Impurity B, and Impurity C, or a salt thereof. In someembodiments, the salt is a methanesulfonic acid salt.

In some embodiments, the impurity in Compound 1 is an alcohol solvent.In some embodiments, the alcohol solvent is methanol, ethanol,n-propanol, or isopropanol.

In some embodiments, the impurity in Compound 1 is toluene.

In some embodiments, the impurity in Compound 1 is acetone, ethylacetate, or methyl t-butyl ether. In some embodiments, the impurity iswater. In some embodiments of the compound of the invention, theimpurity is a solvent.

In some embodiments, the purity of methanesulfonic acid is at leastabout 99% by weight, and methanesulfonic acid comprises no more thanabout 1% of an impurity by weight of the methanesulfonic acid. In someembodiments, the purity of methanesulfonic acid is about 95.0% to 100%by weight, and methanesulfonic acid comprises 0% to about 5.0% of animpurity by weight of the methanesulfonic acid. In some embodiments, thepurity of methanesulfonic acid is about 98% to 100% by weight, andmethanesulfonic acid comprises 0% to about 2% of an impurity by weightof the methanesulfonic acid. In some embodiments, the purity ofmethanesulfonic acid is about 98%, about 98.5%, about 99%, about 99.5%,or 100% by weight, and methanesulfonic acid comprises about 2%, about1.5%, about 1%, about 0.5%, or 0%, respectively, of an impurity byweight of the methanesulfonic acid. In some embodiments, the purity orthe impurity is determined by high-performance liquid chromatography(HPLC). In some embodiments, the impurity is determined by titration.

In some embodiments, the purity of methanesulfonic acid is at leastabout 99%, and methanesulfonic acid comprises no more than about 1% ofan impurity by chromatographic area of the methanesulfonic acid peak, asdetermined by GC. In some embodiments, the purity of methanesulfonicacid is about 95.0% to 100%, and comprises 0% to about 5.0% of animpurity by chromatographic area of the methanesulfonic acid peak asdetermined by GC. In some embodiments, the purity of methanesulfonicacid is about 98% to 100%, and methanesulfonic acid comprises 0% toabout 2% of an impurity by chromatographic area of the methanesulfonicacid peak, as determined by GC. In some embodiments, the purity ofCompound 1 is about 98%, about 98.5%, about 99%, about 99.5%, or 100%,and methanesulfonic acid comprises about 2%, about 1.5%, about 1%, about0.5%, or 0%, respectively, of an impurity by chromatographic area of themethanesulfonic acid peak as determined by GC. In some embodiments,methanesulfonic acid comprises less than about 0.5% solvent asdetermined by GC. In some embodiments, methanesulfonic acid comprisesless than about 0.3% solvent as determined by GC.

In some embodiments, methanesulfonic acid comprises less than 1% or lessthan 0.5% of an impurity by weight of the methanesulfonic acid. In someembodiments, methanesulfonic acid comprises less than 1%, less than0.9%, less than 0.8%, less than 0.7%, less than 0.6%, less than 0.5%,less than 0.4%, less than 0.3%, less than 0.2%, or less than 0.1% of animpurity by weight of the methanesulfonic acid. In some embodiments,methanesulfonic acid comprises no more than 1% or no more than 0.5% ofan impurity by weight of the methanesulfonic acid. In some embodiments,methanesulfonic acid comprises no more than 1%, no more than 0.9%, nomore than 0.8%, no more than 0.7%, no more than 0.6%, no more than 0.5%,no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than0.1% of an impurity by weight of the methanesulfonic acid. In someembodiments, the impurity is determined by high-performance liquidchromatography (HPLC). In some embodiments, the impurity is determinedby titration.

In some embodiments, the impurity in methanesulfonic acid is an alkylmethanesulfonate. In some embodiments of the compounds of the invention,the alkyl methanesulfonate is methyl methanesulfonate, ethylmethanesulfonate, n-propyl methanesulfonate, or isopropylmethanesulfonate.

In some embodiments, the impurity in methanesulfonic acid is an alcoholsolvent. In some embodiments, the alcohol solvent is methanol, ethanol,n-propanol, or isopropanol.

In some embodiments, the impurity in methanesulfonic acid is toluene.

In some embodiments, the impurity in methanesulfonic acid is acetone,ethyl acetate, or methyl t-butyl ether. In some embodiments, theimpurity is water. In some embodiments of the compound of the invention,the impurity is a solvent.

In some embodiments, the methods of the invention do not comprisesubjecting the compound of the invention to further purification. Insome embodiments, the methods of the invention do not comprise furtherpurifying the compound of the invention.

Compounds of the Invention

In some embodiments, the compound of the invention is isolatedphentolamine mesylate, filtered phentolamine mesylate or driedphentolamine mesylate.

In some embodiments, a compound of the invention is hygroscopic.

In some embodiments, a compound of the invention is stored or storableunder inert gas. In some embodiments, inert gas is argon. In someembodiments, inert gas is nitrogen.

In some embodiments, a compound of the invention is hydroscopic and isstored or storable under an inert gas, e.g., nitrogen or argon.

In some embodiments, the compound of the invention is crystalline.

In some embodiments, the compound of the invention exhibits an X-raypowder diffraction (XRPD) pattern comprising a peak at about 6.87±0.2degrees 2-theta, a peak at about 20.32±0.2 degrees 2-theta, and a peakat about 21.36±0.2 degrees 2-theta. In some embodiments, the compound ofthe invention exhibits an XRPD pattern further comprising a peak atabout 18.86±0.2 degrees 2-theta and a peak at about 21.07±0.2 degrees2-theta. In some embodiments, the compound of the invention exhibits anXRPD pattern further comprising a peak at about 11.65±0.2 degrees2-theta, at about 13.15±0.2 degrees 2-theta, and a peak at about20.85±0.2 degrees 2-theta. In some embodiments, the compound of theinvention exhibits an XRPD pattern further comprising a peak at about20.05±0.2 degrees 2-theta and a peak at about 23.87±0.2 degrees 2-theta.In some embodiments, the compound of the invention exhibits an XRPDpattern further comprising a peak at about 18.47±0.2 degrees 2-theta anda peak at about 19.38±0.2 degrees 2-theta. In some embodiments, thecompound of the invention exhibits an XRPD pattern further comprising apeak at about 14.71±0.2 degrees 2-theta and a peak at about 22.22±0.2degrees 2-theta.

In some embodiments, the compound of the invention exhibits an XRPDpattern comprising a peak at about 20.32±0.2 degrees 2-theta and a peakat about 21.36±0.2 degrees 2-theta. In some embodiments, the compound ofthe invention exhibits an XRPD pattern further comprising a peak atabout 18.86±0.2 degrees 2-theta and a peak at about 13.15±0.2 degrees2-theta. In some embodiments, the compound of the invention exhibits anXRPD pattern further comprising a peak at about 18.47±0.2 degrees2-theta and a peak at about 20.05±0.2 degrees 2-theta. In someembodiments, the compound of the invention exhibits an XRPD patternfurther comprising a peak at about 22.22±0.2 degrees 2-theta and a peakat about 23.24±0.2 degrees 2-theta. In some embodiments, the compound ofthe invention exhibits an XRPD pattern further comprising a peak atabout 16.70±0.2 degrees 2-theta and a peak at about 21.70±0.2 degrees2-theta. In some embodiments, the compound of the invention exhibits anXRPD pattern further comprising a peak at about 8.42±0.2 degrees 2-thetaand a peak at about 8.53±0.2 degrees 2-theta.

In some embodiments, the compound of the invention exhibits an XRPDpattern comprising 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks,7 peaks, 8 peaks, 9 peaks, or 10 peaks of Table 1. In some embodiments,the compound of the invention exhibits an XRPD pattern comprising 1peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9peaks, or 10 peaks of the following peaks: a peak at about 13.15±0.2degrees 2-theta, a peak at about 16.70±0.2 degrees 2-theta, a peak atabout 18.47±0.2 degrees 2-theta, a peak at about 18.86±0.2 degrees2-theta, a peak at about 20.05±0.2 degrees 2-theta, a peak about20.32±0.2 degrees 2-theta, a peak at about 21.36±0.2 degrees 2-theta, apeak at about 21.70±0.2 degrees 2-theta, a peak at about 22.22±0.2degrees 2-theta and a peak at about 23.24±0.2 degrees 2-theta.

In some embodiments, the compound of the invention exhibits an XRPDpattern comprising a peak from Table 1 having a peak relative intensity(%) of greater than 70%. In some embodiments, the compound of theinvention exhibits an XRPD pattern comprising a peak from Table 1 havinga peak relative intensity (%) of greater than 50%. In some embodiments,the compound of the invention exhibits an XRPD pattern comprising a peakfrom Table 1 having a peak relative intensity (%) of greater than 30%.

In some embodiments, the compound of the invention exhibits an XRPDpattern comprising 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks,7 peaks, 8 peaks, 9 peaks, or 10 peaks of Table 3.

In some embodiments, the compound of the invention exhibits an XRPDpattern that is substantially the same as that depicted in FIG. 1 .

In some embodiments, the compound of the invention does not exhibit anXRPD pattern that is substantially the same as that depicted in FIG. 3 .

In some embodiments, the compound of the invention comprises less than5% of phentolamine mesylate exhibiting an XRPD pattern substantially thesame as that depicted in FIG. 3 , by weight of the compound of theinvention. In some embodiments, the compound of the invention comprisesless than 4% of phentolamine mesylate exhibiting an XRPD patternsubstantially the same as that depicted in FIG. 3 , by weight of thecompound of the invention. In some embodiments, the compound of theinvention comprises less than 2% of phentolamine mesylate exhibiting anXRPD pattern substantially the same as that depicted in in FIG. 3 , byweight of the compound of the invention. In some embodiments, thecompound of the invention comprises less than 1% of phentolaminemesylate exhibiting an XRPD pattern substantially the same as thatdepicted in FIG. 3 , by weight of the compound of the invention. In someembodiments, the compound of the invention comprises less than 0.5% ofphentolamine mesylate exhibiting an XRPD pattern substantially the sameas that depicted in in FIG. 3 , by weight of the compound of theinvention.

In some embodiments, the compound of the invention exhibits adifferential scanning calorimetry (DSC) thermogram comprising anendothermic peak having a peak maximum at about 180° C. In someembodiments, the compound of the invention exhibits a DSC thermogramcomprising an endothermic peak that onsets at about 176° C.

In some embodiments, the compound of the invention exhibits a DSCthermogram comprising an endothermic peak having a peak maximum at about120° C. In some embodiments, the compound of the invention exhibits aDSC thermogram comprising an endothermic peak that onsets at about 108°C.

In some embodiments, the compound of the invention exhibits a DSCthermogram comprising an endothermic peak having a peak maximum at about133° C. In some embodiments, the compound of the invention exhibits aDSC thermogram comprising an endothermic peak that onsets at about 129°C.

In some embodiments, the compound of the invention exhibits a DSCthermogram comprising an endothermic peak having a peak maximum at about120° C. and a peak maximum at about at about 180° C. In someembodiments, the compound of the invention exhibits a DSC thermogramcomprising an endothermic peak that onsets at about 108° C. and anendothermic peak that onsets at about 176° C.

In some embodiments, the compound of the invention exhibits a DSCthermogram comprising an exothermic peak having a peak maximum betweenabout 245° C. and about 250° C.

In some embodiments, the compound of the invention exhibits a DSCthermogram that is substantially the same as that depicted in FIG. 2 .

In some embodiments, the compound of the invention exhibits athermo-gravimetric (TG) thermogram that is substantially the same asthat depicted in FIG. 2 .

In some embodiments, the compound of the invention does not exhibit aDSC thermogram that is substantially the same as that depicted in FIG. 4.

In some embodiments, the compound of the invention does not exhibit a TGthermogram that is substantially the same as that depicted in FIG. 4 .

In some embodiments, the compound of the invention comprises less thanabout 20% of amorphous phentolamine mesylate by weight or mole of thecompound of the invention. In some embodiments, the compound of theinvention comprises less than about 15% of amorphous phentolaminemesylate by weight or mole of the compound of the invention. In someembodiments, the compound of the invention comprises less than about 10%of amorphous phentolamine mesylate by weight or mole of the compound ofthe invention. In some embodiments, the compound of the inventioncomprises less than about 5% of amorphous phentolamine mesylate byweight or mole of the compound of the invention.

In some embodiments, the compound of the invention has a molar ratio ofcrystalline phentolamine mesylate to amorphous phentolamine mesylate ofat least 4:1. In some embodiments, the compound of the invention has amolar ratio of crystalline phentolamine mesylate to amorphousphentolamine mesylate of at least 5:1. In some embodiments, the compoundof the invention has a molar ratio of crystalline phentolamine mesylateto amorphous phentolamine mesylate of at least 17:3. In someembodiments, the compound of the invention has a molar ratio ofcrystalline phentolamine mesylate to amorphous phentolamine mesylate ofat least 6:1. In some embodiments, the compound of the invention has amolar ratio of crystalline phentolamine mesylate to amorphousphentolamine mesylate of at least 7:1. In some embodiments, the compoundof the invention has a molar ratio of crystalline phentolamine mesylateto amorphous phentolamine mesylate of at least 8:1. In some embodiments,the compound of the invention has a molar ratio of crystallinephentolamine mesylate to amorphous phentolamine mesylate of at least9:1. In some embodiments, the compound of the invention has a molarratio of crystalline phentolamine mesylate to amorphous phentolaminemesylate of at least 10:1. In some embodiments, the compound of theinvention has a molar ratio of crystalline phentolamine mesylate toamorphous phentolamine mesylate of at least 11:1. In some embodiments,the compound of the invention has a molar ratio of crystallinephentolamine mesylate to amorphous phentolamine mesylate of at least23:2. In some embodiments, the compound of the invention has a molarratio of crystalline phentolamine mesylate to amorphous phentolaminemesylate of at least 12:1. In some embodiments, the compound of theinvention has a molar ratio of crystalline phentolamine mesylate toamorphous phentolamine mesylate of at least 13:1. In some embodiments,the compound of the invention has a molar ratio of crystallinephentolamine mesylate to amorphous phentolamine mesylate of at least93:7. In some embodiments, the compound of the invention has a molarratio of crystalline phentolamine mesylate to amorphous phentolaminemesylate of at least 14:1. In some embodiments, the compound of theinvention has a molar ratio of crystalline phentolamine mesylate toamorphous phentolamine mesylate of at least 15:1. In some embodiments,the compound of the invention has a molar ratio of crystallinephentolamine mesylate to amorphous phentolamine mesylate of at least16:1. In some embodiments, the compound of the invention has a molarratio of crystalline phentolamine mesylate to amorphous phentolaminemesylate of at least 17:1. In some embodiments, the compound of theinvention has a molar ratio of crystalline phentolamine mesylate toamorphous phentolamine mesylate of at least 18:1. In some embodiments,the compound of the invention has a molar ratio of crystallinephentolamine mesylate to amorphous phentolamine mesylate of at least19:1. In some embodiments, the compound of the invention has a molarratio of crystalline phentolamine mesylate to amorphous phentolaminemesylate of at least 20:1.

The present invention further provides a compound of invention that isat least about 98% (weight %) of the compound of the invention, and acompound of the invention comprises no more than about 2% of an impurity(weight %) of the compound of the invention. In some embodiments, thepurity of a compound of the invention is about 95.0% to 100%, and acompound of the invention comprises 0% to about 5% of an impurity byweight of the compound of the invention. In some embodiments, the purityof a compound of the invention is about 98% to 100%, and a compound ofthe invention comprises 0% to about 2% of an impurity by weight of thecompound of the invention. In some embodiments, the purity of a compoundof the invention is about 98%, about 98.5%, about 99%, about 99.5%, or100%, and a compound of the invention comprises about 2%, about 1.5%,about 1%, about 0.5%, or 0%, respectively, of an impurity by weight ofthe compound of the invention, after drying. In some embodiments, thepurity of a compound of the invention is about 99.5%, about 99.9%, orabout 99.95%, and a compound of the invention comprises about 0.5%,about 0.1%, or about 0.05%, respectively, of an impurity by weight ofthe compound of the invention, after drying. In some embodiments, thepurity of a compound of the invention is about 98%, about 98.5%, about99%, about 99.5%, or 100%, and a compound of the invention comprisesabout 2%, about 1.5%, about 1%, about 0.5%, or 0%, respectively, of animpurity by weight of the compound of the invention, after drying byrotary evaporator. In some embodiments, the purity of a compound of theinvention is about 99.5%, about 99.9%, or about 99.95%, and a compoundof the invention comprises about 0.5%, about 0.1%, or about 0.05%,respectively, of an impurity by weight of the compound of the invention,after drying by rotary evaporator. In some embodiments, the purity of acompound of the invention is about 98%, about 98.5%, about 99%, about99.5%, or 100%, and a compound of the invention comprises about 2%,about 1.5%, about 1%, about 0.5%, or 0%, respectively, of an impurity byweight of the compound of the invention, after lyophilizing. In someembodiments, the impurity is determined by high-performance liquidchromatography (HPLC). In some embodiments, the impurity is determinedby titration.

In some embodiments, the compound of invention comprises less than about1% of an impurity by weight of the compound of the invention. In someembodiments, the compound of invention comprises less than about 0.5% ofan impurity by weight of the compound of the invention. In someembodiments, the compound of invention comprises less than about 1%,less than about 0.9%, less than about 0.8%, less than about 0.7%, lessthan about 0.6%, less than about 0.5%, less than about 0.4%, less thanabout 0.3%, or less than about 0.2% of an impurity by weight of thecompound of the invention.

In some embodiments, the purity determination of a compound of theinvention by HPLC comprises comparing a compound of the invention to areference sample of phentolamine mesylate having a certified purity. Insome embodiments, the purity of a compound of the invention isdetermined by HPLC as being about 95% to about 102%, in someembodiments, about 95% to about 100%. In some embodiments, the purity ofa compound of the invention determined by HPLC accounts for onlyimpurity that can be detected by the HPLC method used. In someembodiments, the purity determined by HPLC of a compound of theinvention does not account for presence of solvent, if any.

In some embodiments, the purity of a compound of the invention isdetermined by HPLC using a mobile phase that is 0.5 g/L ammonium acetatein a water:acetonitrile (67:33) solution. In some embodiments, the HPLCmethod used in determining the purity of a compound of the inventioncomprises using a detector set at about 220 nm to about 230 nm.

In some embodiments, the purity of a compound of the invention is atleast about 98%, and a compound of the invention comprises no more thanabout 2% of an impurity by chromatographic area of the peak of thecompound of the invention, as determined by gas chromatography (GC). Insome embodiments, the purity of a compound of the invention is about95.0% to 100%, and a compound of the invention comprises no more than 0%to about 5.0% of an impurity by chromatographic area of the peak of thecompound of the invention, as determined by GC. In some embodiments, thepurity of a compound of the invention is about 98% to 100%, and acompound of the invention comprises 0% to about 2% of an impurity bychromatographic area of the peak of the compound of the invention, asdetermined by GC. In some embodiments, the GC method used in determiningthe purity of a compound of the invention comprises United StatesPharmacopeia (USP) Method <467>. In some embodiments, a compound of theinvention comprises less than about 0.5% solvent as determined by GC. Insome embodiments, a compound of the invention comprises less than about0.3% solvent as determined by GC. In some embodiments, a compound of theinvention comprises less than about 0.5% or less than about 0.3% solventas determined by GC, after drying. In some embodiments, a compound ofthe invention comprises less than about 0.5% or less than about 0.3%solvent as determined by GC, after lyophilizing.

In some embodiments, a compound of the invention comprises less than1.5% of an impurity by weight of the compound of the invention. In someembodiments, a compound of the invention comprises less than 1% of animpurity by weight of the compound of the invention. In someembodiments, a compound of the invention comprises less than 0.5% of animpurity by weight of the compound of the invention. In someembodiments, the impurity is Compound 1. In some embodiments, theimpurity is determined by high-performance liquid chromatography (HPLC).In some embodiments, the impurity is determined by titration.

In some embodiments, a compound of the invention does not comprise adetectable amount of an alkyl methanesulfonate. In some embodiments thedetectable amount is detectable by GC, HPLC, or titration.

In some embodiments, the alkyl methanesulfonate is methylmethanesulfonate, ethyl methanesulfonate, n-propyl methanesulfonate, orisopropyl methanesulfonate.

In some embodiments, a compound of the invention comprises less thanabout 8% water by weight as determined by Karl Fischer titration. Insome embodiments, a compound of the invention comprises less than about6% water by weight of the compound of the invention, as determined byKarl Fischer titration. In some embodiments, a compound of the inventioncomprises less than about 2% water by weight as determined by KarlFischer titration. In some embodiments, a compound of the inventioncomprises less than about 1% water by weight of the compound of theinvention, as determined by Karl Fischer titration. In some embodiments,a compound of the invention comprises less than about 0.5% water byweight of the compound of the invention, as determined by Karl Fischertitration. In some embodiments, a compound of the invention comprisesless than about 8%, less than about 7.5%, less than about 7%, less thanabout 6.5%, less than about 6%, less than about 5.5%, less than about5%, less than about 4.5%, less than about 4%, less than about 3.5%, lessthan about 3%, less than about 2.5%, less than about 2%, less than about1.5%, less than about 1%, or less than about 0.5% water by weight of thecompound of the invention, as determined by Karl Fischer titration.

In some embodiments, a compound of the invention comprises less thanabout 8% or less than about 6% water by weight of the compound of theinvention, as determined by Karl Fischer titration, after drying. Insome embodiments, a compound of the invention comprises less than about8% or less than about 6% water by weight of the compound of theinvention, as determined by Karl Fischer titration, after drying byrotary evaporator.

In some embodiments, a compound of the invention comprises less thanabout 2% or less than about 1% water by weight of the compound of theinvention, as determined by Karl Fischer titration, after drying. Insome embodiments, a compound of the invention comprises less than about2% or less than about 1% water by weight of the compound of theinvention, as determined by Karl Fischer titration, after lyophilizing.

The present invention further provides a compound of invention that isobtained or obtainable as described in Example 1. In some embodiments,the compound of the invention that is obtained or obtainable asdescribed in Example 1 is a crystalline phentolamine mesylate. In someembodiments, the compound of the invention is more than 99% pure withoutsubjecting it to further purification.

The present invention further provides a compound of invention that isobtained or obtainable as described in Example 2. In some embodiments,the compound of the invention that is obtained or obtainable asdescribed in Example 2 is a crystalline phentolamine mesylate. In someembodiments, the compound of the invention is more than 99% pure withoutsubjecting it to further purification.

The present invention further provides a compound of invention that ismade or makable by a synthesis method of the invention.

In some embodiments, a compound of invention does not comprise animpurity. In some embodiments, the compound of the invention does notcomprise a detectable amount of an impurity. In some embodiments, theisolated phentolamine mesylate, filtered phentolamine mesylate, or driedphentolamine mesylate does not comprise a detectable amount of animpurity. In some embodiments, the compound of the invention is morethan 99% pure without subjecting it to further purification. In someembodiments, the isolated phentolamine mesylate, filtered phentolaminemesylate, or dried phentolamine mesylate is more than 99% pure withoutsubjecting it to further purification.

The present invention further provides phentolamine mesylate comprisingless than 1% of an impurity by weight of the phentolamine mesylate. Insome embodiments, the phentolamine mesylate comprises less than 0.5% ofthe impurity by weight of the phentolamine mesylate. In someembodiments, the phentolamine mesylate comprises less than 0.1% of theimpurity by weight of the phentolamine mesylate. In some embodiments,the phentolamine mesylate comprises less than 1% of an impurity byweight, less than 0.9% of an impurity by weight, less than 0.8% of animpurity by weight, less than 0.7% of an impurity by weight, less than0.6% of an impurity by weight, less than 0.5% of an impurity by weight,less than 0.4% of an impurity by weight, less than 0.3% of an impurityby weight, less than 0.2% of an impurity by weight, less than 0.1% of animpurity by weight, or less than 0.05% of an impurity by weight of thephentolamine mesylate. In some embodiments, the phentolamine mesylate isan isolated phentolamine mesylate, a filtered phentolamine mesylate, ora dried phentolamine mesylate that is not subjected to furtherpurification. In some embodiments, the phentolamine mesylate is a driedphentolamine mesylate that is not subjected to further purification.

The present invention further provides phentolamine mesylate comprisingwater in the range of 0% by weight to about 6% by weight of thephentolamine mesylate and comprises less than 1% of an impurity byweight of the phentolamine mesylate. In some embodiments, thephentolamine mesylate comprises less than 0.5% of the impurity by weightof the phentolamine mesylate. In some embodiments, the phentolaminemesylate comprises less than 0.3% of the impurity by weight of thephentolamine mesylate. In some embodiments, the phentolamine mesylatecomprises less than 0.1% of the impurity by weight of the phentolaminemesylate. In some embodiments, the phentolamine mesylate comprises lessthan 1% of the impurity by weight, less than 0.9% of the impurity byweight, less than 0.8% of the impurity by weight, less than 0.7% of theimpurity by weight, less than 0.6% of the impurity by weight, less than0.5% of the impurity by weight, less than 0.4% of the impurity byweight, less than 0.3% of the impurity by weight, less than 0.2% of theimpurity by weight, less than 0.1% of the impurity by weight, or lessthan 0.05% of the impurity by weight of the phentolamine mesylate. Insome embodiments, the phentolamine mesylate comprises 0% water by weightto about 3% water by weight of the phentolamine mesylate. In someembodiments, the phentolamine mesylate comprises 0% water by weight toabout 2% water by weight of the phentolamine mesylate. In someembodiments, the phentolamine mesylate comprises 0% water by weight toabout 1.5% water by weight of the phentolamine mesylate. In someembodiments, the phentolamine mesylate comprises 0% water by weight toabout 6% water by weight of the phentolamine mesylate and comprises lessthan 0.5% of an impurity by weight of the phentolamine mesylate. In someembodiments, the phentolamine mesylate comprises 0% water by weight toabout 6% water by weight of the phentolamine mesylate and comprises lessthan 0.3% of an impurity by weight of the phentolamine mesylate. In someembodiments, the phentolamine mesylate comprises 0% water by weight toabout 3% water by weight of the phentolamine mesylate and comprises lessthan 0.5% of the impurity by weight of the phentolamine mesylate. Insome embodiments, the phentolamine mesylate comprises 0% water by weightto about 2% water by weight of the phentolamine mesylate and comprisesless than 0.5% of an impurity by weight of the phentolamine mesylate. Insome embodiments, the phentolamine mesylate comprises 0% water by weightto about 2% water by weight of the phentolamine mesylate and comprisesless than 0.1% of an impurity by weight of the phentolamine mesylate.

In some embodiments, the impurity is Compound 1.

In some embodiments, the impurity is an alkyl methanesulfonate. In someembodiments of a compounds of the invention, the alkyl methanesulfonateis methyl methanesulfonate, ethyl methanesulfonate, n-propylmethanesulfonate, or isopropyl methanesulfonate.

In some embodiments, the impurity is a process by-product or adegradation product.

In some embodiments, the impurity is Impurity A(N-(2-aminoethyl)-2-[(3-hydroxyphenyl)(4-methylphenyl)amino]-acetamide).

In some embodiments, the impurity is an Impurity A salt. In someembodiments, the impurity is an Impurity A methanesulfonate salt.

In some embodiments, Impurity A is a process by-product or degradationproduct.

In some embodiments, the impurity is Impurity B(2-chloromethyl-4,5-dihydro-1H-imidazole). In some embodiments, theimpurity is an Impurity B salt. In some embodiments, the impurity is anImpurity B methanesulfonate salt.

In some embodiments, Impurity B is a process by-product or degradationproduct.

In some embodiments, the impurity is Impurity C(3-hydroxy-4′-methyldiphenylamine). In some embodiments, the impurity isan Impurity C salt. In some embodiments, the impurity is an Impurity Cmethanesulfonate salt.

In some embodiments, Impurity C is a process by-product. In someembodiments, Impurity C is a degradation product.

In some embodiments, the impurity is one or more of Impurity A, ImpurityB, and Impurity C, or a salt thereof. In some embodiments, the salt is amethanesulfonic acid salt.

In some embodiments of the compounds of the invention, the impurity isan alcohol solvent. In some embodiments of the compounds of theinvention, the alcohol solvent is methanol, ethanol, n-propanol, orisopropanol.

In some embodiments of the compounds of the invention, the impurity istoluene.

In some embodiments of the compounds of the invention, the isolatedphentolamine mesylate, filtered phentolamine mesylate, or driedphentolamine mesylate comprises toluene in an amount of less than 890ppm as determined by GC. In some embodiments of the compounds of theinvention, the isolated phentolamine mesylate, filtered phentolaminemesylate, or dried phentolamine mesylate comprises toluene in an amountof less than 5 ppm, less than 4 ppm, less than 3 ppm, less than 2 ppm,or less than 1 ppm as determined by GC. In some embodiments, theisolated phentolamine mesylate, filtered phentolamine mesylate, or driedphentolamine mesylate does not comprise toluene.

In some embodiments of the compounds of the invention, the isolatedphentolamine mesylate, filtered phentolamine mesylate, or driedphentolamine mesylate comprises acetone in an amount of less than 5000ppm as determined by GC. In some embodiments, the isolated phentolaminemesylate, filtered phentolamine mesylate, or dried phentolamine mesylatecomprises acetone in an amount of less than 1000 ppm, less than 900 ppm,less than 800 ppm, or less than 700 ppm as determined by GC.

In some embodiments of the compounds of the invention, the isolatedphentolamine mesylate, filtered phentolamine mesylate, or driedphentolamine mesylate comprises ethyl acetate in an amount of less than5000 ppm as determined by GC. In some embodiments, the isolatedphentolamine mesylate, filtered phentolamine mesylate, or driedphentolamine mesylate comprises ethyl acetate in an amount of less than100 ppm, less than 90 ppm, less than 80 ppm, less than 70 ppm, less than60 ppm, less than 50 ppm, less than 40 ppm, or less than 30 ppm asdetermined by GC.

In some embodiments of the compounds of the invention, the isolatedphentolamine mesylate, filtered phentolamine mesylate, or driedphentolamine mesylate comprises methyl t-butyl ether in an amount ofless than 5000 ppm as determined by GC. In some embodiments, theisolated phentolamine mesylate, filtered phentolamine mesylate, or driedphentolamine mesylate comprises methyl t-butyl ether in an amount ofless than 200 ppm, less than 180 ppm, less than 160 ppm, less than 140ppm, less than 120 ppm, or less than 110 ppm as determined by GC.

In some embodiments of the compounds of the invention, the impurity iswater.

In some embodiments, the isolated phentolamine mesylate, filteredphentolamine mesylate, or dried phentolamine mesylate comprises animpurity that is no more than 5% by weight of the phentolamine mesylate.

In some embodiments, the isolated phentolamine mesylate, filteredphentolamine mesylate, or dried phentolamine mesylate comprises animpurity that is no more than 4.5%, no more than 4%, no more than 3.5%,no more than 3%, no more than 2.5%, no more than 2%, no more than 1.5%,or no more than 1% by weight of the phentolamine mesylate.

In some embodiments, the impurity is Compound 1.

In some embodiments, the impurity is an alkyl methanesulfonate. In someembodiments of the compounds of the invention, the alkylmethanesulfonate is methyl methanesulfonate, ethyl methanesulfonate,n-propyl methanesulfonate, or isopropyl methanesulfonate.

In some embodiments, the impurity is a process by-product or adegradation product.

In some embodiments, the impurity is Impurity A(N-(2-aminoethyl)-2-[(3-hydroxyphenyl)(4-methylphenyl)amino]-acetamide).In some embodiments, the impurity is an Impurity A salt. In someembodiments, the impurity is an Impurity A methanesulfonate salt.

In some embodiments, Impurity A is a process by-product or degradationproduct.

In some embodiments, the impurity is Impurity B(2-chloromethyl-4,5-dihydro-1H-imidazole). In some embodiments, theimpurity is an Impurity B salt. In some embodiments, the impurity is anImpurity B methanesulfonate salt. In some embodiments, Impurity B is aprocess by-product or degradation product.

In some embodiments, the impurity is Impurity C(3-hydroxy-4′-methyldiphenylamine). In some embodiments, the impurity isan Impurity C salt. In some embodiments, the impurity is an Impurity Cmethanesulfonate salt. In some embodiments, Impurity C is a processby-product. In some embodiments, Impurity C is a degradation product.

In some embodiments, the impurity is one or more of Impurity A, ImpurityB, and Impurity C, or a salt thereof. In some embodiments, the salt is amethanesulfonic acid salt.

In some embodiments of the compounds of the invention, the impurity isan alcohol solvent. In some embodiments of the compounds of theinvention, the alcohol solvent is methanol, ethanol, n-propanol, orisopropanol.

In some embodiments of the compounds of the invention, the impurity istoluene.

In some embodiments of the compounds of the invention, the isolatedphentolamine mesylate, filtered phentolamine mesylate, or driedphentolamine mesylate comprises toluene in an amount of no more than 890ppm as determined by GC. In some embodiments of the compounds of theinvention, the isolated phentolamine mesylate, filtered phentolaminemesylate, or dried phentolamine mesylate comprises toluene in an amountof no more than 5 ppm, no more than 4 ppm, no more than 3 ppm, no morethan 2 ppm, or no more than 1 ppm as determined by GC.

In some embodiments of the compounds of the invention, the isolatedphentolamine mesylate, filtered phentolamine mesylate, or driedphentolamine mesylate comprises acetone in an amount of no more than5000 ppm as determined by GC. In some embodiments, the isolatedphentolamine mesylate, filtered phentolamine mesylate, or driedphentolamine mesylate comprises acetone in an amount of no more than1000 ppm, no more than 900 ppm, no more than 800 ppm, or no more than700 ppm as determined by GC.

In some embodiments of the compounds of the invention, the isolatedphentolamine mesylate, filtered phentolamine mesylate, or driedphentolamine mesylate comprises ethyl acetate in an amount of no morethan 5000 ppm as determined by GC. In some embodiments, the isolatedphentolamine mesylate, filtered phentolamine mesylate, or driedphentolamine mesylate comprises ethyl acetate in an amount of no morethan 100 ppm, no more than 90 ppm, no more than 80 ppm, no more than 70ppm, no more than 60 ppm, no more than 50 ppm, no more than 40 ppm, orno more than 30 ppm as determined by GC.

In some embodiments of the compounds of the invention, the isolatedphentolamine mesylate, filtered phentolamine mesylate, or driedphentolamine mesylate comprises methyl t-butyl ether in an amount of nomore than 5000 ppm as determined by GC. In some embodiments, theisolated phentolamine mesylate, filtered phentolamine mesylate, or driedphentolamine mesylate comprises methyl t-butyl ether in an amount of nomore than 200 ppm, no more than 180 ppm, no more than 160 ppm, no morethan 140 ppm, no more than 120 ppm, or no more than 110 ppm asdetermined by GC.

In some embodiments, the purity of the isolated phentolamine mesylate,filtered phentolamine mesylate, or dried phentolamine mesylate is atleast about 98% (weight %), and comprises no more than about 2% of animpurity by weight of the phentolamine mesylate. In some embodiments,the purity or the impurity are determined by high-performance liquidchromatography (HPLC). In some embodiments, the impurity is determinedby titration.

In some embodiments, the purity of the isolated phentolamine mesylate,filtered phentolamine mesylate, or dried phentolamine mesylate is about95.0% to 100% by weight, and the isolated phentolamine mesylate,filtered phentolamine mesylate, or dried phentolamine mesylate comprises0% to about 5.0% of an impurity by weight of the phentolamine mesylate.In some embodiments, the purity of the isolated phentolamine mesylate,filtered phentolamine mesylate, or dried phentolamine mesylate is about98% to 100% by weight, and the isolated phentolamine mesylate, filteredphentolamine mesylate, or dried phentolamine mesylate comprises 0% toabout 2% of an impurity by weight of the phentolamine mesylate. In someembodiments, the purity of the isolated phentolamine mesylate, filteredphentolamine mesylate, or dried phentolamine mesylate is about 98%,about 98.5%, about 99%, about 99.5%, or 100% by weight, and the isolatedphentolamine mesylate, filtered phentolamine mesylate, or driedphentolamine mesylate comprises about 2%, about 1.5%, about 1%, about0.5%, or 0%, respectively, of an impurity by weight of the phentolaminemesylate. In some embodiments, the purity or the impurity are determinedby high-performance liquid chromatography (HPLC). In some embodiments,the impurity is determined by titration.

In some embodiments of the compounds of the invention, the purity of theisolated phentolamine mesylate, filtered phentolamine mesylate, or driedphentolamine mesylate is at least about 98%, and the isolatedphentolamine mesylate, filtered phentolamine mesylate, or driedphentolamine mesylate comprises no more than about 2% of an impurity bychromatographic area of the peak of the compound of the invention, asdetermined by GC. In some embodiments, the purity of the isolatedphentolamine mesylate, filtered phentolamine mesylate, or driedphentolamine mesylate is about 95.0% to 100%, and comprises 0% to about5.0% of an impurity by chromatographic area of the peak of the compoundof the invention, as determined by GC. In some embodiments, the purityof the isolated phentolamine mesylate, filtered phentolamine mesylate,or dried phentolamine mesylate is about 98% to 100%, and the isolatedphentolamine mesylate, filtered phentolamine mesylate, or driedphentolamine mesylate comprises 0% to about 2% of an impurity bychromatographic area of the peak of the compound of the invention, asdetermined by GC. In some embodiments, the purity of the isolatedphentolamine mesylate, filtered phentolamine mesylate, or driedphentolamine mesylate is about 98%, about 98.5%, about 99%, about 99.5%,or 100%, and the isolated phentolamine mesylate, filtered phentolaminemesylate, or dried phentolamine mesylate comprises about 2%, about 1.5%,about 1%, about 0.5%, or 0%, respectively, of an impurity bychromatographic area of the peak of the compound of the invention asdetermined by GC. In some embodiments, the isolated phentolaminemesylate, filtered phentolamine mesylate, or dried phentolamine mesylatecomprises less than about 0.5% solvent as determined by GC. In someembodiments, the isolated phentolamine mesylate, filtered phentolaminemesylate, or dried phentolamine mesylate comprises less than about 0.3%solvent as determined by GC.

In some embodiments of the compounds of the invention, the isolatedphentolamine mesylate, filtered phentolamine mesylate, or driedphentolamine mesylate comprises less than 1.5% of an impurity by weightof the compound of the invention. In some embodiments, the isolatedphentolamine mesylate, filtered phentolamine mesylate, or driedphentolamine mesylate comprises less than 1% of an impurity by weight ofthe compound of the invention. In some embodiments, the isolatedphentolamine mesylate, filtered phentolamine mesylate, or driedphentolamine mesylate comprises less than 0.5% of an impurity by weightof the compound of the invention. In some embodiments, the impurity isCompound 1. In some embodiments, the impurity is one or more of ImpurityA, Impurity B, and Impurity C, or a salt thereof. In some embodiments,the salt is a methanesulfonic acid salt. In some embodiments, theimpurity is determined by high-performance liquid chromatography (HPLC).In some embodiments, the impurity is determined by titration.

In some embodiments of the compounds of the invention, the isolatedphentolamine mesylate, filtered phentolamine mesylate, or driedphentolamine mesylate comprises less than about 8% water by weight ofthe compound of the invention, as determined by Karl Fischer titration.In some embodiments, the isolated phentolamine mesylate, filteredphentolamine mesylate, or dried phentolamine mesylate comprises lessthan about 6% water by weight of the compound of the invention, asdetermined by Karl Fischer titration. In some embodiments, the isolatedphentolamine mesylate, filtered phentolamine mesylate, or driedphentolamine mesylate comprises less than about 1% water by weight ofthe compound of the invention, as determined by Karl Fischer titration.In some embodiments, the isolated phentolamine mesylate, filteredphentolamine mesylate, or dried phentolamine mesylate comprises lessthan about 8%, less than about 7.5%, less than about 7%, less than about6.5%, less than about 6%, less than about 5.5%, less than about 5%, lessthan about 4.5%, less than about 4%, less than about 3.5%, less thanabout 3%, less than about 2.5%, less than about 2%, less than about1.5%, less than about 1%, or less than about 0.5% water by weight of thecompound of the invention, as determined by Karl Fischer titration.

In some embodiments, the invention provides compositions comprising acompound of the invention and an impurity, wherein the impurity ispresent in the composition in an amount of no more than 0.5% by weight,mole or volume of the composition. In some embodiments, the inventionprovides compositions comprising the compound of the invention and animpurity, wherein the impurity is present in the composition in anamount of no more than 0.4%, no more than 0.3%, no more than 0.2%, or nomore than 0.1% of the mixture, by weight, mole or volume of thecomposition.

In some embodiments, the impurity is Compound 1.

In some embodiments, the impurity is an alkyl methanesulfonate. In someembodiments of the compounds of the invention, the alkylmethanesulfonate is methyl methanesulfonate, ethyl methanesulfonate,n-propyl methanesulfonate, or isopropyl methanesulfonate.

In some embodiments, the impurity is a process by-product or adegradation product.

In some embodiments, the impurity is Impurity A(N-(2-aminoethyl)-2-[(3-hydroxyphenyl)(4-methylphenyl)amino]-acetamide).In some embodiments, the impurity is an Impurity A salt. In someembodiments, the impurity is an Impurity A methanesulfonate salt.

In some embodiments, Impurity A is a by-product or degradation product.

In some embodiments, the impurity is Impurity B(2-chloromethyl-4,5-dihydro-1H-imidazole). In some embodiments, ImpurityB is a process byproduct. In some embodiments, the impurity is anImpurity B salt. In some embodiments, the impurity is an Impurity Bmethanesulfonate salt.

In some embodiments, the impurity is Impurity C(3-hydroxy-4′-methyldiphenylamine). In some embodiments, Impurity C is aprocess by-product or degradation product. In some embodiments, ImpurityC is a degradation product. In some embodiments, the impurity is anImpurity C salt. In some embodiments, the impurity is an Impurity Cmethanesulfonate salt.

In some embodiments, the impurity is one or more of Impurity A, ImpurityB, and Impurity C, or a salt thereof. In some embodiments, the salt is amethanesulfonic acid salt.

In some embodiments of the compounds of the invention, the impurity isan alcohol solvent. In some embodiments of the compounds of theinvention, the alcohol solvent is methanol, ethanol, n-propanol, orisopropanol.

In some embodiments of the compounds of the invention, the impurity istoluene.

In some embodiments of the compounds of the invention, the impurity isacetone, ethyl acetate, or methyl t-butyl ether. In some embodiments,the impurity is water. In some embodiments of the compounds of theinvention, the impurity is a solvent.

The present invention further provides a sealed container containing acompound of the invention and an inert gas. In some embodiments, theinert gas is argon or nitrogen.

The present invention further provides a sealed container containing theisolated phentolamine mesylate and an inert gas. In some embodiments,the inert gas is argon or nitrogen.

The present invention further provides a sealed container containing thefiltered phentolamine mesylate and an inert gas. In some embodiments,the inert gas is argon or nitrogen.

The present invention further provides a sealed container containing thedried phentolamine mesylate and an inert gas. In some embodiments, theinert gas is argon or nitrogen.

Therapeutic Methods of the Invention

In some embodiments, the compound of the invention is useful forinhibiting the contraction of smooth muscle of the iris. Accordingly,the invention further provides methods for inhibiting the contraction ofsmooth muscle of the iris, comprising administering to a subject in needthereof an effective amount of the compound of the invention.

In some embodiments, the compound of the invention is useful forreducing pupil diameter. Accordingly, the invention further providesmethods for reducing pupil diameter, comprising administering to asubject in need thereof an effective amount of the compound of theinvention.

In some embodiments, the compound of the invention is useful forimproving visual contrast sensitivity or visual acuity. Accordingly, theinvention further provides methods for improving visual contrastsensitivity or visual acuity, comprising administering to a subject inneed thereof an effective amount of the compound of the invention.

In some embodiments, the compound of the invention is useful fortreating a dim or night vision disturbance. Accordingly, the inventionfurther provides methods for treating a dim or night vision disturbance,comprising administering to a subject in need thereof an effectiveamount of the compound of the invention.

In some embodiments, the compound of the invention is useful fortreating or reversing pharmacologically induced mydriasis. Accordingly,the invention further provides methods for treating or reversingpharmacologically induced mydriasis, comprising administering to asubject in need thereof an effective amount of the compound of theinvention.

In some embodiments, the compound of the invention is useful fortreating presbyopia. Accordingly, the invention further provides methodsfor treating presbyopia, comprising administering to a subject in needthereof an effective amount of the compound of the invention.

In some embodiments, the administering is topically instilling into asubject's eye.

In some embodiments, the effective amount of the compound of theinvention is about 0.01 mg to about 100 mg. In some embodiments, theeffective amount of the compound of the invention is about 0.05 mg toabout 50 mg. In some embodiments, the effective amount of the compoundof the invention is about 0.1 mg to about 100 mg. In some embodiments,the effective amount of the compound of the invention is about 1 mg toabout 25 mg. In some embodiments, the effective amount of the compoundof the invention is about 5 mg to about 10 mg.

In some embodiments, the effective amount of the compound of theinvention is about 0.1 mg to about 2.0 mg, about 0.2 mg to about 0.7 mg,about 0.4 mg to about 0.6 mg, or about 0.8 mg to about 1.2 mg. In someembodiments, the effective amount of the compound of the invention isabout 0.5 mg or about 1 mg.

In some embodiments, the effective amount of the compound of theinvention is about 0.1 mg to about 2.0 mg. In some embodiments, theeffective amount of the compound of the invention is about 0.1 mg toabout 1.0 mg. In some embodiments, the effective amount of the compoundof the invention is about 0.2 mg to about 0.7 mg. In some embodiments,the effective amount of the compound of the invention is about 0.4 mg toabout 0.6 mg. In some embodiments, the effective amount of the compoundof the invention is about 0.25 mg, about 0.5 mg or about 1.0 mg. In someembodiments, the effective amount of the compound of the invention isabout 0.5 mg.

Pharmaceutical Compositions

In some embodiments, the compound of the invention is present in acomposition. In some embodiments, the composition is a pharmaceuticalcomposition. In some embodiments, the compositions comprise a compoundof the invention and a pharmaceutically acceptable carrier or excipient.

In some embodiments, the compositions are formulated for administrationby a variety of means including orally, parenterally, by inhalationspray, topically, or rectally. The term “parenteral” as used hereincludes subcutaneous, intravenous, intramuscular, and intraarterialinjections with a variety of infusion techniques. Intraarterial andintravenous injection as used herein includes administration throughcatheters.

In some embodiments, the composition is a solution, a suspension, anemulsion, a tablet, a pill, a capsule, a powder, a cream, or a gel.

In some embodiments, the pharmaceutical composition is an ophthalmicsolution. In some embodiments, the ophthalmic solution comprises acompound of the invention in about 0.5% to about 2% by weight of theophthalmic solution. In some embodiments, the ophthalmic solutioncomprises a compound of the invention in an amount that is molarequivalent to about 0.5% to about 5% of Compound 1 by weight or volumeof the ophthalmic solution. In some embodiments, the ophthalmic solutioncomprises a compound of the invention in an amount that is molarequivalent to about 0.35% or about 1% of Compound 1 by weight or volumeof the ophthalmic solution. In some embodiments, the ophthalmic solutioncomprises a compound of the invention in an amount that is molarequivalent to about 0.37% or about 0.5% of Compound 1 by weight orvolume of the ophthalmic solution. In some embodiments, the ophthalmicsolution comprises a compound of the invention in an amount of about0.35% or about 0.75% by weight or volume of the ophthalmic composition.

In some embodiments, the composition comprises about 1% of phentolaminemesylate by weight of the composition. In some embodiments, thecomposition comprises about 1% of phentolamine mesylate by volume of thecomposition. In some embodiments, the composition is an ophthalmiccomposition.

In some embodiments, the composition comprises about 0.5% ofphentolamine mesylate by weight of the composition. In some embodiments,the composition comprises about 0.5% of phentolamine mesylate by volumeof the composition. In some embodiments, the composition is anophthalmic composition.

In some embodiments, the ophthalmic solution is suitable for ocularadministration or ophthalmic use. In some embodiments, the ophthalmicsolution is suitable for topical, subconjunctival, intravitreal,retrobulbar, intracameral or systemic administration.

In some embodiments, the pharmaceutically acceptable carrier or vehicleis a stabilizer, binder, filler, diluent, disintegrant, wetting agent,lubricant, glidant, coloring agent, dye-migration inhibitor, sweeteningagent, flavoring agent, viscosity modifying agent, pH adjusting agent,buffer, osmotic agent, chelating agent, surfactants, or co-solvent.

In some embodiments, a viscosity modifying agent is polyvinyl alcohol,poloxamers, hyaluronic acid, carbomers, and polysaccharides, that is,cellulose derivatives, gellan gum, or xanthan gum.

In some embodiments, the pharmaceutically acceptable carrier or vehicleis sterile water, sterile buffer solution, or sterile saline.

In some embodiments, the pharmaceutically acceptable carrier or vehiclecomprises or is mannitol or sodium acetate.

In some embodiments, the compositions of the invention comprise apreservative. In some embodiments, the preservative is benzalkoniumchloride, cetrimide, polyquatemium-1, thimerosal, sodium perborate,stabilized oxychloro complex, stabilized chlorite peroxide,chlorhexidine, chlorobutanol, phenylethanol or methylparaben.

In some embodiments, the compositions of the invention do not comprise apreservative. In some embodiments, the compositions are preservativefree.

In some embodiments, the compositions of the invention have a pH in therange of about 4 to about 6. In some embodiments, the compositions ofthe invention have a pH in the range of about 4.5 to about 5.3. In someembodiments, the compositions have a pH of about 4.5, about 4.6, about4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, or about5.3.

In some embodiments, a composition of the invention is contained in asealed container. In some embodiments, the sealed container furthercontains an inert gas. In some embodiments, the inert gas is argon ornitrogen.

In some embodiments, the compositions of the invention are useful forinhibiting the contraction of smooth muscle of the iris. Accordingly,the invention further provides methods for inhibiting the contraction ofsmooth muscle of the iris, comprising administering to a subject in needthereof an effective amount of a composition of the invention.

In some embodiments, the compositions of the invention are useful forreducing pupil diameter. Accordingly, the invention further providesmethods for reducing pupil diameter, comprising administering to asubject in need thereof an effective amount of a composition of theinvention.

In some embodiments, the compositions of the invention are useful forimproving visual contrast sensitivity or visual acuity. Accordingly, theinvention further provides methods for improving visual contrastsensitivity or visual acuity, comprising administering to a subject inneed thereof an effective amount of a composition of the invention.

In some embodiments, the compositions of the invention are useful fortreating a dim or night vision disturbance. Accordingly, the inventionfurther provides methods for treating a dim or night vision disturbance,comprising administering to a subject in need thereof an effectiveamount of a composition of the invention.

In some embodiments, the compositions of the invention are useful fortreating or reversing pharmacologically induced mydriasis. Accordingly,the invention further provides methods for treating or reversingpharmaceutically induced mydriasis, comprising administering to asubject in need thereof an effective amount of a composition of theinvention.

In some embodiments, the compositions of the invention are useful fortreating presbyopia. Accordingly, the invention further provides methodsfor treating presbyopia, comprising administering to a subject in needthereof an effective amount of a composition of the invention.

In some embodiments, the administering is topically instilling into thesubject's eye.

EXAMPLES Example 1. Synthesis of Phentolamine Mesylate from Compound 1

To a suspension of3-[[(4,5-dihydro-1H-imidazol-2-yl)methyl](4-methylphenyl)amino] phenol(Compound 1; 145 g, 515.35 mmol) in a mixture of acetone (1560 mL) andwater (134 mL) was added methanesulfonic acid (54.5 g, 567 mmol, 1.1equiv.) over 20 min under argon atmosphere. The temperature of reactionmixture spontaneously increased from 20° C. to 29.4° C. The reactionmixture became clear solution, and the reaction mixture was allowed tocontinue to stir at room temperature for 0.5 h. Methyl t-butyl ether(MTBE; 1450 mL) was added to the reaction mixture. The resultant mixturewas cooled to 0±3° C. at a rate of about 1.33° C./minute for about 15minutes. Phentolamine mesylate began to precipitate from the mixturewhen it reached a temperature of about 11° C. After reaching 0±3° C.,the mixture was maintained at this temperature for 1 h, further cooledto −20±3° C. at a rate of about 1° C./minute for about twenty minutesand maintained at −20±3° C. for 3 h with stirring. The precipitate wascollected by vacuum filtration, washed with MTBE (435 mL), dried using a1-L rotavapor at 43° C. under reduced pressure (40 mbar) for 48 hoursand further dried via lyophilization to provide3-[[(4,5-dihydro-1H-imidazol-2-yl)methyl](4-methyl phenyl)amino]phenolmesylate (phentolamine mesylate; 171 g, yield: 87.9%) as a white solid.HPLC: 99.95%. ¹H NMR (300 MHz, DMSO-d₆/TMS): δ 9.99 (s, 2H), 9.31 (s,1H), 7.18 (d, J=8.1 Hz, 2H), 7.08 (d, J=8.1 Hz, 2H), 7.02 (t, J=8.1 Hz,1H), 6.33 (dd, J=7.2 Hz, J=1.8 Hz, 1H), 6.24 (dd, J=7.2 Hz, J=1.8 Hz,1H), 6.20 (s, 1H), 4.73 (s, 2H), 3.81 (s, 4H), 2.30 (s, 3H), 2.27 (s,3H). ¹³C NMR (75 MHz, DMSO-d₆/TMS): δ 170.2, 158.6, 149.2, 144.5, 133.9,130.5, 130.3, 124.3, 108.7, 108.6, 105.4, 49.3, 44.9, 20.8.

Example 2. Synthesis of Phentolamine Mesylate from Compound 1

To a suspension of3-[[(4,5-dihydro-1H-imidazol-2-yl)methyl](4-methylphenyl)amino] phenol(Compound 1; 828 g, 2.91 mmol) in a mixture of acetone (8900 mL) andwater (765 mL) was added methanesulfonic acid (311 g, 3.21 mol, 1.1equiv.) over 30 minutes under argon atmosphere. The temperature ofreaction mixture was spontaneously increased from 15.7° C. to 26° C. Thereaction mixture became clear, and the reaction mixture was allowed tocontinue to stir at room temperature for 0.5 h. MTBE (8280 mL) was addedto the above reaction mixture. The resultant mixture was cooled to 0±3°C. at a rate of about 1.33° C./minute for about 15 minutes. Phentolaminemesylate began to precipitate from the mixture when it reached atemperature of about 11° C. After reaching 0±3° C., the mixture wasmaintained at this temperature for 1 h, further cooled to −20±3° C. at arate of about 1° C./minute for about twenty minutes and maintained at−20±3° C. for 3 h with stirring. The resultant precipitate was collectedby vacuum filtration, washed with MTBE (1240 mL×2), dried using a 10-Lrotavapor at 43° C. under reduced pressure (40 mbar) for 5 h and then at6 mbar for 5 h to provide3-[[(4,5-dihydro-1H-imidazol-2-yl)methyl](4-methyl phenyl)amino]phenolmesylate (phentolamine mesylate; 956.2 g, yield: 86.6%) as off-whitesolid. HPLC: 99.55%. ¹H NMR (300 MHz, DMSO-d₆/TMS): δ 9.99 (s, 2H), 9.31(s, 1H), 7.18 (d, J=8.1 Hz, 2H), 7.08 (d, J=8.1 Hz, 2H), 7.02 (t, J=8.1Hz, 1H), 6.33 (dd, J=7.2 Hz, J=1.8 Hz, 1H), 6.24 (dd, J=7.2 Hz, J=1.8Hz, 1H), 6.20 (s, 1H), 4.73 (s, 2H), 3.81 (s, 4H), 2.30 (s, 3H), 2.27(s, 3H). ¹³C NMR (75 MHz, DMSO-d₆/TMS): δ 170.2, 158.6, 149.2, 144.5,133.9, 130.5, 130.3, 124.3, 108.7, 108.6, 105.4, 49.3, 44.9, 20.8.

X-ray powder diffraction (XRPD) analysis was carried out using a BrukerD8 Discover diffractometer with DAVINCI configuration, in transmissionmode (scan type: TwoTheta or Offset Coupled TwoTheta/Theta) scanningabout 5 mg phentolamine mesylate obtained according to Example 2 atbetween 1.5 and 45° 20 angles, and using the following measurementscharacteristics: acquisition time was 53 minutes, increment per step was0.01°, time per step was 0.7 s, and generator voltage/generator amperagewas 40 mA/40 kV to reach 1.6 kW power.

The raw data was imported in the Diffrac.EVA5.0 software and it wasprocessed using the subsequent parameters: background subtraction andKα2 stripping were performed before peak determination, and the peaksearch operation was performed with a threshold of 1 and a peak width of0.153 for the sample. Only the resulting peaks having relative intensitygreater than 2% were considered. The degree of crystallinity wascalculated using the Diffrac.EVA5.0 software option. The degree ofcrystallinity of the phentolamine mesylate obtained according to Example2 was 91.5% with 8.5% amorphous phase, indicating that the material hasa high degree of crystallinity.

FIG. 1 shows an XRPD diffractogram of the phentolamine mesylate obtainedas described in Example 2, and Table 1 lists XRPD peaks represented inFIG. 1 .

TABLE 1 Angle 2θ (°) Net Intensity (counts) Rel. Intensity (%) 6.57805.22 14.95 6.87 5206.82 96.67 8.42 893.45 16.59 8.53 901.65 16.74 8.91532.10 9.88 10.11 117.23 2.18 10.91 133.62 2.48 11.17 308.59 5.73 11.651889.71 35.08 12.59 144.89 2.69 13.15 1821.07 33.81 14.71 1189.28 22.0815.37 751.55 13.95 15.77 127.26 2.36 16.34 439.51 8.16 16.70 949.2717.62 16.91 771.33 14.32 18.47 1068.87 19.84 18.86 3141.95 58.33 19.381238.07 22.99 20.05 1172.06 21.76 20.32 4672.35 86.74 20.85 2119.2939.35 21.07 2173.39 40.35 21.36 5386.33 100.00 21.70 911.37 16.92 22.07778.80 14.46 22.22 973.63 18.08 22.95 176.18 3.27 23.24 955.36 17.7423.53 257.04 4.77 23.87 1368.83 25.41 24.50 480.43 8.92 24.65 333.876.20 25.51 290.85 5.40 26.11 193.68 3.60 26.36 338.79 6.29 27.09 592.2411.00 27.42 368.10 6.83 27.63 728.26 13.52 27.90 269.32 5.00 28.50164.20 3.05 28.98 124.03 2.30 29.43 321.41 5.97 29.91 191.28 3.55 30.43209.46 3.89 31.24 196.52 3.65 31.56 122.73 2.28 31.91 437.68 8.13 32.10347.49 6.45 32.31 436.38 8.10 32.53 423.20 7.86 33.14 218.06 4.05 33.26216.37 4.02 35.14 436.48 8.10 36.33 182.53 3.39 37.57 109.35 2.03 37.89209.42 3.89 38.43 113.71 2.11 39.61 111.10 2.06 40.36 193.23 3.59

Thermo-gravimetric (TG)/differential scanning calorimetric (DSC)analysis was carried out. A sample of phentolamine mesylate (about 9 mg)obtained according to Example 2 was weighed into an open aluminum pan,loaded into a simultaneous Setaram LABSYS EVOthermo-gravimetric/differential scanning calorimeter (TG-DTA/DSC) andmaintained at 30° C. for 15 minutes. The sample was then heated from 30°C. to 550° C., during which time a change in sample weight was recordedalong with any differential thermal events. Nitrogen was used as a purgegas, at a flow rate of 180 cm³/min. Prior to the analysis, theinstrument mass loss and temperature were calibrated using coppersulfate pentahydrate and reference standards (lead and indium),respectively. The sample analysis was carried out with the help ofCALISTO software, where the corresponding mass loss and temperatures ofthermal events were quoted as the onset temperature, measured accordingto the manufacturer's specifications. The analysis was carried out witha heating rate of 10° C./minute and the background was subtracted beforefurther processing.

The TG/DSC analysis showed 3 endothermic events (peak maxima at about120° C., 133° C., and about 180° C.) and one exothermic event (FIG. 2 ).

The TG/DSC analysis did not show any thermic event that indicates orsuggests that the sample lost water.

Example 3. Comparison of Powder XRPD Patterns and TG/DSC Thermograms

The XRPD analysis and TG/DSC analysis of commercially available UnitedStates Pharmacopeia (USP) reference standard phentolamine mesylate(purity: 99.5%) were carried out as described in Example 2. The XRPDpattern and the TG/DSC thermograms of the phentolamine mesylate USPreference standard were compared to those of the phentolamine mesylateobtained according to Example 2.

The degree of crystallinity of the phentolamine mesylate USP referencestandard was 85.1% with 14.9% amorphous phase, compared to thephentolamine mesylate obtained according to Example 2, which has adegree of crystallinity of 91.5% with 8.5% amorphous phase.

FIG. 3 shows an XRPD diffractogram of the phentolamine mesylate USPreference standard, and Table 2 lists XRPD peaks represented in FIG. 3 .

TABLE 2 Angle 2θ (°) Net Intensity (counts) Rel. Intensity (%) 6.67287.05 6.10 6.92 656.31 13.95 8.26 113.50 2.41 8.57 380.56 8.09 10.17128.57 2.73 11.22 258.56 5.50 11.71 1718.23 36.53 14.73 328.32 6.9815.44 662.52 14.09 16.76 797.82 16.96 16.94 125.17 2.66 17.80 127.992.72 18.14 149.55 3.18 18.59 1108.99 23.58 18.94 1423.19 30.26 19.22267.97 5.70 19.54 577.37 12.28 20.40 4703.14 100.00 20.66 373.47 7.9421.15 1970.68 41.90 21.42 3983.23 84.69 21.76 877.82 18.66 22.14 575.1512.23 22.33 148.16 3.15 22.91 124.08 2.64 23.33 750.03 15.95 23.931355.51 28.82 24.58 488.33 10.38 24.70 303.72 6.46 26.15 225.95 4.8026.53 163.51 3.48 27.19 185.76 3.95 27.69 797.21 16.95 27.99 224.00 4.7629.07 126.74 2.69 29.57 195.09 4.15 31.27 167.71 3.57 31.99 228.62 4.8632.39 331.96 7.06 32.64 259.17 5.51 33.23 140.20 2.98 33.41 210.77 4.4834.31 97.99 2.08 37.97 102.05 2.17 38.53 94.74 2.01 40.43 196.96 4.19

Table 3 lists selected peaks of the XRPD pattern of the phentolaminemesylate obtained according to Example 2.

TABLE 3 Angle 2θ (°) Net Intensity (counts) Rel. Intensity (%) 8.91532.1 9.88 10.91 133.62 2.48 12.59 144.89 2.69 13.15 1821.07 33.81 16.34439.51 8.16 25.51 290.85 5.4 28.50 164.2 3.05 29.91 191.28 3.55 30.43209.46 3.89 31.56 122.73 2.28 35.14 436.48 8.1 36.33 182.53 3.39

The TG/DSC analysis showed one endothermic event (peak maximum at about183° C.) and one exothermic event (FIG. 4 ).

Based on the TG/DSC data, both phentolamine mesylate obtained accordingto Example 2 and the phentolamine mesylate USP reference standard areanhydrous.

1.-50. (canceled)
 51. Phentolamine mesylate comprising 0% water byweight to about 6% water by weight of the phentolamine mesylate andcomprising less than 0.3% of another impurity by weight of thephentolamine mesylate.
 52. The phentolamine mesylate of claim 51,wherein the phentolamine mesylate comprises 0% water by weight to about3% water by weight of the phentolamine mesylate.
 53. The phentolaminemesylate of claim 51, wherein the phentolamine mesylate comprises 0%water by weight to about 2% water by weight of the phentolaminemesylate.
 54. The phentolamine mesylate of any one of claims 51-53,wherein the phentolamine mesylate comprises less than 0.1% of the otherimpurity by weight of the phentolamine mesylate.
 55. The phentolaminemesylate of any one of claims 51-54, wherein the other impurity isCompound
 1. 56. The phentolamine mesylate of any one of claims 51-54,wherein the other impurity is an alkyl methanesulfonate.
 57. Thephentolamine mesylate of any one of claims 51-54, wherein the otherimpurity isN-(2-aminoethyl)-2-[(3-hydroxyphenyl)(4-methylphenyl)amino]-acetamide,2-chloromethyl-4,5-dihydro-1H-imidazole, or3-hydroxy-4′-methyldiphenylamine, or a salt thereof. 58.-93. (canceled)